Study reveals mechanism that worsens tuberculosis and reduces survival

CD4+ T lymphocytes have already been widely described in the scientific literature for their important role in the immune response during pulmonary infections. However, research published in the magazine “Cell Reports” demonstrated that an excessive accumulation of these defense cells in lung tissues – responsible for gas exchange essential for breathing – is associated with damage to the lungs rather than performing a protective function.

The discovery, obtained through mouse models of virulent tuberculosis and influenza, points to the presence of a “ideal amount” of lymphocytes in lung tissue in order to ensure a good outcome of the disease. This finding opens perspectives for therapeutic interventions that aim to reduce the impact on the host without affecting the immune system's ability to fight the infection. Even reduced numbers of CD4+ T cells in the lung have been shown to be sufficient to protect against tuberculosis, for example.

The researchers observed that the accumulation of lymphocytes in lung tissue is mediated by a specific type of receptor, P2RX7, capable of detecting the presence of extracellular ATP (adenosine triphosphate). ATP has an energetic function for the cell, but in contexts of stress or tissue damage it is released into the external environment, acting as a danger signal for defense cells and, in some cases, inducing an excessive response.

P2RX7 induces excessive accumulation of lymphocytes, increasing the expression of CXCR3, a chemokine receptor (proteins that act as chemical signals in the immune system, attracting specific cells to areas where they are needed). According to the study, the accumulation of CD4+ T cells in the lung induced by the activation of P2RX7 is linked to the worsening of the pathology and reduced survival of the animals.

“When this ATP is in the extracellular environment, it is recognized as a sign of damage by the immune system, since the molecule that should be inside the cell has left. Studies had shown its importance for the development of severe forms of tuberculosis, but it was still unknown what the mechanisms were and specifically which cell expressed it most. We started the research from there, however, we always had the intention of improving the response of this cell. What we didn't expect was that, if we removed the receptor blocking ATP recognition, there would be an improvement, not a worsening.”, the doctor in immunology told Agência FAPESP Igor Santiago-Carvalhofrom ICB-USP (Institute of Biomedical Sciences of the University of São Paulo).

First author of the article, Santiago-Carvalho worked under the guidance of the professor Maria Regina D'Império Lima, who has been researching cellular immunology, mainly in malaria, Chagas disease and tuberculosis, for more than 20 years. “The more we can understand which are the main 'players' in the balance between a deficient, optimal and excessive immune response, the greater the chance of manipulating this response through drugs and treatments aimed at better control and outcome of the disease.”, says Lima.

According to the professor, T lymphocytes are “players” important in this process due to their ability to stimulate and regulate the immune response.

“Therefore, we seek to understand which signaling pathways influence this balance. We realized during the project that when the fabric is very damaged, it ends up releasing a large number of signs of damage. We were particularly concerned with ATP and saw that the number of T lymphocytes that entered the tissue upon detecting this molecule was excessive, inducing an intense and damaging inflammatory response. In some cases, it even leads to a fibrotic process in the lung. Interfering with this signaling pathway may be interesting to reduce the damage caused by the excessive immune response against infection.”, he stated.

Gravity

Tuberculosis is still considered an important public health problem, recently worsened by the emergence of antibiotic-resistant bacteria. Infectious and transmissible, the disease primarily affects the lungs.

The most common symptoms are a continuous dry cough, which after 4 weeks may have discharge; excessive tiredness; low fever; night sweats; lack of appetite; and marked weight loss.

The delay in starting treatment, the high virulence of the strains and the patient's susceptibility contribute to the severity of the case, often associated with a deleterious inflammatory response, leading to difficulty breathing and even pulmonary necrosis. Treatment is based on antibiotics for 6 months, with no abandonment or irregularity.

In the world, new diagnosed cases of tuberculosis were a record in 2022, with 7.5 million cases recordswhich represents the highest number since the WHO (World Health Organization) began global monitoring in 1995. The growth was attributed to the expansion of diagnostic and treatment services.

Future

Initially designed to work with tuberculosis, the study also tested the role of CD4+ T-specific P2RX7 in influenza-infected mice. The result was similar.

“This has driven a lot of what I'm doing as I continue to study how signals of damage control immune responses. In the article, we came to the conclusion that CD4+ T cells can be pathogenic. Now we want to understand what leads to the increase in this pathogenesis in order to define it and show the mechanisms behind it, which can be applied to other diseases. Understanding the characteristics of this cell that end up inducing a response so strong as to damage the tissue, it is possible to seek therapeutic alternatives”, explains Santiago-Carvalho.

With information from Fapesp Agency